Our primary hypothesis was that treatment failure at five days among children aged 2-59 months with WHO defined very severe pneumonia was greater for parenteral chloramphenicol than it was for injectable ampicillin plus gentamicin. The primary outcome was treatment failure at five days. Secondary outcomes were treatment failure defined similarly among all participants evaluated at 48 hours and at 10 and 21 days.
This randomised, non-blinded efficacy study was carried out at eight sites in seven countries: Dhaka, Bangladesh; Guayaquil, Ecuador; Chandigarh, India; Mexico City, Mexico; Multan and Rawalpindi, Pakistan; Sana’a, Yemen; and Lusaka, Zambia (box 1). A consensus protocol was developed by investigators from the study sites, WHO, Johns Hopkins University Bloomberg School of Public Health, and the Center for International Health and Development at Boston University School of Public Health.
Box 1: Study sites
- Bangladesh—Bangladesh Institute of Child Health, Dhaka Shishu Hospital, Dhaka
- Ecuador—Dr Francisco de Icaza Bustamente Children’s Hospital, Guayaquil
- India—Post Graduate Institute of Medical Research and Education, Chandigarh
- Mexico—National Institute of Pediatrics, Mexico DF, Jaurez Hospital, Mexico City
- Pakistan—Rawalpindi General Hospital, Rawalpindi, and Nishter Hospital, Multan
- Yemen—Al-Sabeen Hospital, Sana’a University, Sana’a
- Zambia—Department of Paediatrics and Child Health, University Teaching Hospital, Lusaka
Study doctors and study nurses at each site were trained on the study protocol and WHO case management for acute respiratory tract infections using WHO training videos and exercises to ensure inter-rater reliability among the study staff. The clinical investigator at each site oversaw and monitored the study staff.
Box 2 shows the criteria for study inclusion and exclusion. We informed families about the purpose and background of the study, the study procedures, risks, payments, and confidentiality. They were told that they could withdraw their child from the study at any time and that he or she would continue to receive standard medical care provided to children with similar illness in the participating hospital. They were told that during admission to hospital their child would be assessed every six hours or more often if needed, for any change in their condition until there was an improvement in breathing difficulty and satisfactory oxygen levels when breathing room air. They were told about the need for follow-up and when and where to bring the child back to the hospital after discharge to see if they were still infected.
Box 2: Inclusion and exclusion criteria
- Age 2 to 59 months
- History of cough or difficulty breathing, or both
- WHO defined very severe pneumonia30
- Central cyanosis or inability to drink
- Caregiver willingness to consent
- Wheezing, with a history of three or more attacks, or known asthma
- Known heart disease
- Duration of present illness more than 10 days
- History of serious adverse reaction to any of the study drugs
- Previous enrolment in the study
- Admission to hospital for more than 24 hours within past seven days
- Documented evidence of injectable antibiotic treatment for more than 24 hours before enrolment
- Known renal failure or not passed urine during past six hours
- Evidence of cerebral malaria
- Evidence of bacterial meningitis
- Clinical jaundice
- Residence of patient in an area where follow-up was not possible
- Empyema or presence of pneumatocoeles on chest radiograph
WHO prepared lists for randomisation using permuted blocks of variable length (6-8-10), with block sizes presented in random order. Separate randomisation lists were prepared for each site according to nutrition status of the children (severely malnourished, defined by WHO as oedema or severe wasting=weight for height <70% (−3 z score) or severe stunting=height for age <85% (−3 z score) versus not severely malnourished, as assessed during the baseline examination), and individual patient assignments were placed in opaque sealed envelopes. After each patient was selected for study, the next envelope in order of study numbers (that is, in numerical sequence) was opened to determine the treatment assignment: thus the investigator could not know the order of randomisation and was unable to predict the next assignment.
Before opening each envelope the doctor in charge signed and dated the opening flap of the envelope. The card inside, with the patient’s treatment assignment, and the signed envelope were attached to the patient’s study file. To prevent tampering with the randomisation process, envelopes were checked to ensure that the assignment could not be seen before the envelope was opened. During site visits the presence of the signature, date, and time notification was evaluated and compared with the date and time of randomisation recorded in the medical record.
When children were admitted to the hospital we took a standardised baseline history and carried out a physical examination, laboratory evaluations, and chest radiography. Blood was obtained by venepuncture for complete blood count, malaria smear, blood glucose levels, and bacterial culture. Lumbar puncture was done on participants with clinical signs suggestive of bacterial meningitis, and we examined cerebrospinal fluid for total leucocyte count, differential leucocyte count, biochemistry, and bacterial culture by Gram stain.
Case management protocol
Children received the first dose of antibiotics within two hours of enrolment. Those randomised to the ampicillin plus gentamicin arm received ampicillin 200 mg/kg/d in four doses every six hours, and gentamicin 7.5 mg/kg/d as in a single daily dose. Children randomised to the chloramphenicol arm received 75 mg/kg/d given in three doses every eight hours. Study drugs were procured for all sites from the International Dispensary Association, Amsterdam, Holland. Oxygen was delivered at a rate of 1-2 l/min by nasal cannula for children with oxygen saturations less than or equal to 90% (or ≤88% in the two high altitude sites of Yemen and Mexico) and continued for a minimum of three hours. Study doctors assessed the children every six hours using a standardised form, which included vital signs; cardiorespiratory examination; use of oxygen, salbutamol, or antipyretics; and pulse oximetry. If the doctors detected a treatment failure or if they thought that for any reason a change in management was indicated, this was reviewed with the site clinical investigator before a decision was made. An evaluation form was completed at 48-60 hours after randomisation and again at 5-6 days after randomisation, recording any treatment failures that had occurred to these points.
Once children had completed five days of inpatient care and were improved enough for discharge they received ampicillin plus gentamicin daily as an outpatient. The parenteral gentamicin was given once daily at the outpatient clinic or other sites. Sufficient oral amoxicillin (45 mg/kg/d divided into three doses) was provided to complete the remainder of the 10 day course. Likewise, children in the oral chloramphenicol arm were also given sufficient drugs (75 mg/kg/d in three doses) to complete a 10 day course of treatment. The primary caregiver gave the children their oral antibiotics. Adherence to these regimens was assessed by pill counts and return of empty drug vials at follow-up visits.
Follow-up evaluation was at 10-12 days and 21-30 days after discharge. The children were discharged from the study at the completion of the 21-30 day visit and no further information was collected. If children failed to attend for follow-up study staff attempted to assess them at home.
Box 3 provides the definitions of primary and secondary outcomes. Children met the primary outcome of treatment failure after five days of admission if any of the events in the box occurred at any point after randomisation. Any change in antibiotic treatment during this period resulted in classification as treatment failure and the need to change the regimen was assessed clinically and throughout the entire five day period, not just at the end of five days of treatment. The study protocol did not permit modifications of the antibiotic regimen. We used the same definitions and approach for the secondary outcomes of treatment failure as defined in box 3 by 48 hours (allowing data to be collected up to 60 hours) and treatment failure plus relapse (hypoxaemic pneumonia) by day 10 (allowing data to be collected up to day 12) and by day 30 (allowing data to be collected between study days 21-30).
Box 3: Primary and secondary outcome measures
Primary outcome: treatment failure by five days after admission
- New development or persistence of at least two of the following: inability to drink; tachypnoea (≥50 breaths/min in children aged 2-11 months and ≥40 breaths/min in children aged 12-59 months), and abnormally sleepy or difficult to wake
- Development or diagnosis of any of the following: bacterial meningitis, empyema, septic shock, renal failure, or newly diagnosed comorbid conditions
- Serious adverse drug reaction
- Modification of antibiotic treatment
- Voluntary withdrawal or absconding
- Treatment failure as defined above at 48-60 hours
- Treatment failure as defined above plus relapse (hypoxaemic pneumonia at 10-12 days and 21-30 days, with oxygen saturations ≤90%, or ≤88% in the two high altitude sites in Mexico and Yemen)
- Death by 30 days after enrolment
- Bacterial pathogens isolated from blood or other sterile sites
- Antimicrobial susceptibility of the isolated pathogens
When the study physician suspected treatment failure (see box 3), the physician contacted the principal investigator or coinvestigator for confirmation. At that time the antibiotic was changed and other appropriate treatment provided. Additional chest radiographs, blood counts, blood cultures, and other laboratory tests to aid patient management according to clinical judgment and the usual practices of the participating site were obtained. Broad guidelines for the management of children who failed study treatment were:
Cloxacillin or oxacillin (25-50 mg/kg intravenously every six hours) were added to the regimen. The duration of treatment to be at least two weeks. Empyema was managed with chest tube drainage.
Pneumocystis carinii (now Pneumocystis jiroveci) pneumonia
Cotrimoxazole (with trimethoprim 20 mg/kg/d in two divided doses) and steroids were added to the treatment regimen. The duration of treatment was for at least two weeks.
Non responsive Gram negative infection
If infection with Gram negative bacilli unresponsive to the study regimen was suspected on the basis of clinical deterioration or development of shock, a third generation cephalosporin such as cefotaxime (100-200 mg/kg/d in four divided doses) or ceftriaxone (100-150 mg/kg/d in a single dose) was used. Ceftriaxone was provided by the study.
Mechanical ventilation was provided, when available, to patients with treatment failure and persistent cyanosis while receiving supplemental oxygen.
Standard microbiological techniques31
were used to isolate and identify S pneumoniae
and H influenzae
. The minimum inhibitory concentration of ampicillin, gentamicin, and chloramphenicol for both H influenzae
and S pneumoniae
was determined by E test according to the manufacturer’s instructions (AB Biodisk, Solna, Sweden).
Data management procedures
Data were double entered and validated locally with CENTRY software (US Census Bureau, Washington, DC). We sent original copies of the data to the Data Coordinating Center at Boston University, where the electronic data were cleaned and discrepancies resolved.
The sample size of 1182 participants was based on finding a 30% or greater reduction in treatment failure with ampicillin plus gentamicin compared with an expected 25% baseline failure rate with chloramphenicol,27 32,33,34,35
a 1:1 allocation ratio, 80% power, an α level of 0.05, and two planned interim analyses for early stopping with O’Brien-Fleming end points.36 37
We analysed the data using SAS software. PROC FREQ was used to calculate relative risks and 95% confidence intervals. To identify risk factors predictive of treatment failure by day 5 and death by day 30, we selected a group of factors—immunisation status, sex, hypoxaemia (oxygen saturation ≤90%, or ≤88% in the two high altitude sites in Mexico and Yemen), blood glucose, central cyanosis, age, weight for age z score, and breastfeeding status—and we calculated relative risks. We then included all variables with statistically significant relative risks in a multivariate logistic regression model built using a backward elimination procedure with PROC LOGISTIC. Treatment group and study site were forced into the model and we retained all variables with a Wald P value of 0.20 or less. We used the GLIMMIX macro to calculate the final multivariate models, in which study site was included as a random effect. Because diagnostics are not available for the random effects model we report model diagnostics (area under the receiver operating curve characteristic and Hosmer and Lemeshow goodness of fit test) for a fixed effects model.